Project Summary/Abstract We propose to purchase an integrated single-crystal X-ray diffraction system. This equipment will allow researchers at UT Southwestern Medical Center (UTSW) to robotically screen protein, protein/nucleic acid and nucleic acid single crystals for diffraction properties, and to rapidly and accurately collect diffraction data. Included in the proposed equipment is an automated tool for screening and data collection on crystals grown in situ (i.e., in crystallization screening trays) that will enable high- throughput fragment-based screening of potential pharmaceutical candidates, a capability that is not currently available at UTSW. An upgrade to a currently installed sample mounting robot will reduce the time required for robotic exchange of samples by approximately 50%. The proposed system is optimized for the analysis of small crystals (<100 microns), which will benefit users that work on important biomedical projects (e.g, integral membrane proteins, large eukaryotic protein complexes, protein/nucleic acid complexes) that are difficult to obtain in the large quantities of pure samples required for extensive crystal size optimization. UTSW has a thriving Structural Biology community, consisting of 8 Major Users and 5 Minor Users as well as approximately 20 additional users that access the UTSW X-ray facility via the Structural Biology Laboratory (SBL), a unique core facility that allows any researcher on campus to engage in crystallographic projects without having to establish instrumentation or initial expertise. The proposed equipment will be housed in the centralized campus X-ray facility and will be maintained and operated by the SBL staff of two research-track faculty and a research technician, all funded locally. Modern X-ray diffraction equipment is crucial for maintaining and augmenting our program to provide structural information for diverse basic and translational research. As one of the basic pillars of biomedical research, Structural Biology is vital for understanding many diseases on a molecular level. Structural Biology often serves as a basis for devising therapeutic strategies, for example through structure-based drug design. The X-ray diffraction system that we propose for purchase will help to facilitate these aims.